CN114573457A - Preparation method of malonic half ester - Google Patents

Preparation method of malonic half ester Download PDF

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CN114573457A
CN114573457A CN202210308729.XA CN202210308729A CN114573457A CN 114573457 A CN114573457 A CN 114573457A CN 202210308729 A CN202210308729 A CN 202210308729A CN 114573457 A CN114573457 A CN 114573457A
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malonate
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ester
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杨旭
赵相柱
高爱红
王瑞菲
唐晓婵
张晓霞
刘友彬
王灏
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Qingdao University of Science and Technology
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    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/30Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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Abstract

本发明公开了丙二酸半酯的制备方法,在催化剂存在下,可将丙二酸酯进行选择性水解得到半酯化合物。本发明的选择性单水解反应相较于其他合成丙二酸半酯的方法,反应条件简单,温和,副反应少。利用催化剂来促进丙二酸酯的单水解反应,反应活性高,收率高,具有巨大的应用潜力。The invention discloses a method for preparing a half-ester of malonate. In the presence of a catalyst, the half-ester compound can be obtained by selective hydrolysis of the malonate. Compared with other methods for synthesizing malonic acid half-ester, the selective monohydrolysis reaction of the present invention has simple reaction conditions, mildness and few side reactions. Using a catalyst to promote the monohydrolysis reaction of malonate has high reaction activity and high yield, and has great potential for application.

Description

一种丙二酸半酯的制备方法A kind of preparation method of malonic acid half ester

技术领域technical field

本发明涉及一种丙二酸半酯的制备方法,还具体来说是利用纳米氧化锌作为催化剂丙二酸酯进行碱性水解反应得到丙二酸半酯。The invention relates to a preparation method of a malonic acid half-ester, in particular to the use of nano-zinc oxide as a catalyst for the alkaline hydrolysis reaction of the malonic acid ester to obtain the malonic acid half-ester.

背景技术Background technique

半酯是分子上同时具有酯基和羧基两种结构的化合物,它是许多重要化合物合成过程中的必要材料之一,如药物、天然产物、聚合物等,因此半酯的合成方法一直受到许多科研工作者的关注。半酯的合成方法有环状酸酐的开环,对称二酯的单水解反应等。环状酸酐的开环反应通常需要在干燥的无水有机溶剂条件下进行,如甲苯、苯、醚或氯仿,反应条件苛刻。相对来说,对称二酯的单水解反应,反应条件简单,可以在水溶液中进行,也更符合绿色化学的时代追求。对称二酯的单水解反应,在不断的探索中。Half-ester is a compound with both ester and carboxyl structures on the molecule. It is one of the necessary materials in the synthesis of many important compounds, such as drugs, natural products, polymers, etc. Therefore, the synthesis of half-esters has been subject to many attention of researchers. The synthesis methods of half-esters include ring-opening of cyclic acid anhydrides, monohydrolysis of symmetrical diesters, etc. The ring-opening reaction of the cyclic acid anhydride usually needs to be carried out in a dry anhydrous organic solvent, such as toluene, benzene, ether or chloroform, and the reaction conditions are harsh. Relatively speaking, the single hydrolysis reaction of the symmetrical diester has simple reaction conditions and can be carried out in an aqueous solution, which is more in line with the pursuit of green chemistry. The monohydrolysis reaction of symmetrical diesters is under constant exploration.

半酯分子同时具有酯基和羧基两种结构,酯基和羧基的不同反应活性,是构建许多化合物的重要前驱体。丙二酸一甲酯和丙二酸一乙酯,它们都是许多药物和天然产物合成的重要中间体,是有机合成中最常用的半酯,应用二酯高效选择性单水解,两种半酯都可得较高的产率。这种选择性单水解反应相较于其他合成丙二酸半酯的方法,反应条件是环境友好和简单的,因为它只需要水,一小部分挥发性的共溶剂和便宜的试剂,而且不产生有害的副产品,因此该反应在化学合成中用途是可观的。Half-ester molecules have two structures of ester group and carboxyl group at the same time, and the different reactivity of ester group and carboxyl group is an important precursor for the construction of many compounds. Monomethyl malonate and monoethyl malonate, which are important intermediates in the synthesis of many drugs and natural products, are the most commonly used half-esters in organic synthesis. esters in higher yields. Compared to other methods for the synthesis of malonic acid half-esters, this selective monohydrolysis reaction is environmentally friendly and simple because it only requires water, a small fraction of volatile co-solvents and inexpensive reagents, and does not require Harmful by-products are produced, so this reaction is of considerable use in chemical synthesis.

发明内容SUMMARY OF THE INVENTION

针对现有技术存在的不足,本发明提供了一种利用纳米氧化锌作为催化剂丙二酸酯进行碱性水解反应得到丙二酸半酯的方法。In view of the deficiencies in the prior art, the present invention provides a method for using nano-zinc oxide as a catalyst malonate to carry out an alkaline hydrolysis reaction to obtain a half-ester of malonate.

本发明具体技术方案如下:The specific technical scheme of the present invention is as follows:

一种一种丙二酸半酯的制备方法,其制备方法如下:A kind of preparation method of malonic acid half ester, its preparation method is as follows:

Figure 100002_DEST_PATH_IMAGE001
Figure 100002_DEST_PATH_IMAGE001

具体步骤:丙二酸酯反应底物在催化剂和稀碱的作用下进行水解反应,得到丙二酸单酯化合物。Specific steps: the malonate reaction substrate is hydrolyzed under the action of a catalyst and a dilute base to obtain a malonate monoester compound.

进一步的,丙二酸酯反应底物中R为C1-C5,优选为R为C1;催化剂为纳米氧化锌,粒径为10-500 nm,优选200 nm;稀碱为 NaOH, LiOH, KOH, Ca(OH)2的其中一种或多种,浓度为0.1-5.0 mol/L。Further, R in the malonate reaction substrate is C1-C5, preferably R is C1; the catalyst is nano-zinc oxide, the particle size is 10-500 nm, preferably 200 nm; the dilute base is NaOH, LiOH, KOH, One or more of Ca(OH)2, the concentration is 0.1-5.0 mol/L.

进一步的,丙二酸酯反应底物与催化剂、碱的摩尔比为1:0.5%-2%:1-10,优选为1:1%:2。Further, the molar ratio of the malonate reaction substrate to the catalyst and the base is 1:0.5%-2%:1-10, preferably 1:1%:2.

进一步的,将反应底物、催化剂、碱在有机溶剂中加热回流反应。Further, the reaction substrate, catalyst and base are heated and refluxed in an organic solvent for reaction.

进一步的,反应时间为3-8 h;反应溶剂,所述的有机溶剂为丙酮、四氢呋喃、甲苯的其中一种或多种,溶剂的用量为丙二酸酯反应底物质量的10倍。Further, the reaction time is 3-8 h; the reaction solvent, the organic solvent is one or more of acetone, tetrahydrofuran, and toluene, and the amount of the solvent is 10 times the mass of the malonate reaction substrate.

进一步的,反应结束后过滤分离出固体,反应溶液加入稀盐酸调节溶液Ph值为3,分液收集有机相,水相经乙酸乙酯萃取,乙酸乙酯的用量与溶剂的用量相同。合并有机相,有机相经无水硫酸镁干燥后进行减压蒸馏得到反应产物。Further, after the reaction is completed, the solid is separated by filtration, the reaction solution is added with dilute hydrochloric acid to adjust the pH value of the solution to 3, the organic phase is collected by liquid separation, the aqueous phase is extracted with ethyl acetate, and the consumption of ethyl acetate is the same as that of the solvent. The organic phases were combined, and the organic phases were dried over anhydrous magnesium sulfate and then distilled under reduced pressure to obtain the reaction product.

本发明利用催化剂来促进丙二酸酯的单水解反应,反应活性高,收率高,具有巨大的应用潜力。The present invention utilizes a catalyst to promote the monohydrolysis reaction of malonate, has high reaction activity and high yield, and has great application potential.

具体实施方式Detailed ways

下面通过具体实施例进一步说明本发明,但本发明并不限于此,具体保护范围见权利要求。The present invention is further described below through specific embodiments, but the present invention is not limited thereto, and the specific protection scope is shown in the claims.

实施例1Example 1

将10克丙二酸二甲酯,1%摩尔量的纳米氧化锌, 2倍摩尔量的碱溶液,100克有机溶剂加入反应瓶中加热回流反应,反应结束后过滤分离出固体,反应溶液加入稀盐酸调节溶液Ph值为3,反应溶液经100克乙酸乙酯萃取,乙酸乙酯的用量与溶剂的用量相同,有机相经无水硫酸镁干燥后进行减压蒸馏得到反应产物,计算实验收率。为获得多因素各水平的最佳搭配方法,将10-500 nm不同粒径的氧化锌、不同碱类(NaOH, LiOH, KOH)、不同的反应时间与不同的溶剂进行正交实验。10 grams of dimethyl malonate, 1% molar nano-zinc oxide, 2 times the molar amount of alkali solution, 100 grams of organic solvents are added in the reaction flask for heating and refluxing reaction, after the reaction finishes, the solid is filtered and isolated, and the reaction solution adds Dilute hydrochloric acid was used to adjust the pH value of the solution to 3. The reaction solution was extracted with 100 grams of ethyl acetate. The amount of ethyl acetate was the same as that of the solvent. The organic phase was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to obtain the reaction product. The experimental yield was calculated. Rate. In order to obtain the best matching method of various factors and levels, orthogonal experiments were carried out on zinc oxide with different particle sizes of 10-500 nm, different bases (NaOH, LiOH, KOH), different reaction times and different solvents.

表1 正交实验表Table 1 Orthogonal experiment table

Figure 194988DEST_PATH_IMAGE002
Figure 194988DEST_PATH_IMAGE002

实施例2Example 2

将10克丙二酸二乙酯,0.5%摩尔量的纳米氧化锌(200 nm), 10摩尔量的LiOH(1mol/l)碱溶液,100克丙酮加入反应瓶中加热回流反应,反应结束后过滤分离出固体,反应溶液加入稀盐酸调节溶液Ph值为3,反应溶液经100克乙酸乙酯萃取,有机相经无水硫酸镁干燥后进行减压蒸馏得到反应产物,收率为89%。Add 10 g of diethyl malonate, 0.5% molar amount of nano-zinc oxide (200 nm), 10 molar amount of LiOH (1 mol/l) alkaline solution, and 100 g of acetone into the reaction flask to heat under reflux for reaction. The solid was separated by filtration, the pH value of the solution was adjusted to 3 by adding dilute hydrochloric acid, the reaction solution was extracted with 100 g of ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to obtain the reaction product with a yield of 89%.

实施例3Example 3

将10克丙二酸二丙酯,2%摩尔量的纳米氧化锌(200 nm), 5摩尔量的LiOH(1 mol/l)碱溶液,100克丙酮加入反应瓶中加热回流反应,反应结束后过滤分离出固体,反应溶液加入稀盐酸调节溶液Ph值为3,反应溶液经100克乙酸乙酯萃取,有机相经无水硫酸镁干燥后进行减压蒸馏得到反应产物,收率为85%。Add 10 grams of dipropyl malonate, 2% moles of nano-zinc oxide (200 nm), 5 moles of LiOH (1 mol/l) alkaline solution, and 100 grams of acetone into the reaction flask to heat under reflux for reaction, the reaction ends After the solid was separated by filtration, dilute hydrochloric acid was added to the reaction solution to adjust the pH value of the solution to 3, the reaction solution was extracted with 100 g of ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain the reaction product with a yield of 85%. .

实施例4Example 4

将10克丙二酸二戊酯,2%摩尔量的纳米氧化锌(200 nm), 2摩尔量的LiOH(1 mol/l)碱溶液,100克丙酮加入反应瓶中加热回流反应,反应结束后过滤分离出固体,反应溶液加入稀盐酸调节溶液Ph值为3,反应溶液经100克乙酸乙酯萃取,有机相经无水硫酸镁干燥后进行减压蒸馏得到反应产物,收率为81%。Add 10 grams of dipentyl malonate, 2% moles of nano-zinc oxide (200 nm), 2 moles of LiOH (1 mol/l) alkaline solution, and 100 grams of acetone into the reaction flask and heat under reflux for reaction, the reaction ends After the solid was separated by filtration, dilute hydrochloric acid was added to the reaction solution to adjust the pH value of the solution to 3, the reaction solution was extracted with 100 g of ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain the reaction product with a yield of 81%. .

Claims (6)

1. The preparation method of the malonic acid half ester is characterized by comprising the following steps:
carrying out hydrolysis reaction on a malonate reaction substrate under the action of a catalyst and dilute alkali to obtain a malonate monoester compound; the reaction equation is as follows:
Figure DEST_PATH_IMAGE001
r in the malonate reaction substrate is C1-C5, preferably R is C1; the catalyst is nano zinc oxide with the particle size of 10-500 nm, preferably 200 nm; the dilute alkali is NaOH, LiOH, KOH, Ca (OH)2The concentration of one or more of (A) is 0.1-5.0 mol/L.
2. The method for preparing half malonate according to claim 1, characterized in that: the molar ratio of the malonate reaction substrate to the catalyst to the base is 1: 0.5% -2%: 1-10.
3. The method for preparing half malonate according to claim 1, characterized in that: the molar ratio of the malonate reaction substrate to the catalyst to the base is 1: 1%: 2.
4. the method for preparing half malonate according to claim 1, characterized in that: heating and refluxing a reaction substrate, a catalyst and alkali in an organic solvent for reaction.
5. The method for preparing half malonate according to claim 4, characterized in that: the reaction time is 3-8 h; the organic solvent is one or more of acetone, tetrahydrofuran and toluene, and the dosage of the solvent is 10 times of the mass of the malonate reaction substrate.
6. The method for preparing half malonate according to claim 1, characterized in that: and after the reaction is finished, filtering and separating out a solid, adding dilute hydrochloric acid into the reaction solution to adjust the pH value of the solution to be 3, separating liquid and collecting an organic phase, extracting a water phase by using ethyl acetate, combining the organic phase, drying the organic phase by using anhydrous magnesium sulfate, and then carrying out reduced pressure distillation to obtain a reaction product.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110283103A (en) * 2019-06-27 2019-09-27 北京理工大学 A kind of decarboxylation amination of base catalysis prepares amino-acid ester/amide method
WO2021170464A1 (en) * 2020-02-28 2021-09-02 Basf Se Herbicidal malonamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110283103A (en) * 2019-06-27 2019-09-27 北京理工大学 A kind of decarboxylation amination of base catalysis prepares amino-acid ester/amide method
WO2021170464A1 (en) * 2020-02-28 2021-09-02 Basf Se Herbicidal malonamides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHANG RUI 等: "Synthesis of a-Aryl Nitriles through Palladium-Catalyzed Decarboxylative Coupling of Cyanoacetate Salts with Aryl Halides and Triflates", ANGEW. CHEM. INT. ED., 6 April 2011 (2011-04-06), pages 4470 - 4474 *

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